Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Protein Kinases Involved in the Regulation of Wnt/β-catenin Signaling

Wnt/β-catenin 신호를 조절하는 인산화 효소

  • Shin, Eun-Young (Division of Life Science, Korea Basic Science Institute (KBSI)) ;
  • Park, Edmond Changkyun (Division of Life Science, Korea Basic Science Institute (KBSI)) ;
  • Hong, Yeonhee (Division of Life Science, Korea Basic Science Institute (KBSI)) ;
  • Kim, Gun-Hwa (Division of Life Science, Korea Basic Science Institute (KBSI))
  • 신은영 (한국기초과학지원연구원 생명과학연구부) ;
  • 박창균 (한국기초과학지원연구원 생명과학연구부) ;
  • 홍연희 (한국기초과학지원연구원 생명과학연구부) ;
  • 김건화 (한국기초과학지원연구원 생명과학연구부)
  • Received : 2013.06.29
  • Accepted : 2013.07.08
  • Published : 2013.07.30
Download PDF
⟨ Previous Next ⟩

Abstract

The Wnt/${\beta}$-catenin signaling pathway is an evolutionarily conserved signaling network that is critical for embryonic development and adult tissue maintenance. In addition, aberrant activation of Wnt/${\beta}$-catenin signaling is implicated in the formation of various human diseases, including cancers. Thus, study of the underlying molecular mechanism of Wnt/${\beta}$-catenin signaling regulation is important to understand and treat diseases. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Recently, protein kinases have emerged as key regulating components of Wnt/${\beta}$-catenin signaling. In this review, we provide the most recent information on Wnt/${\beta}$-catenin signaling, describe protein kinases involved in Wnt/${\beta}$-catenin signaling, and discuss their potential as drug targets.

Wnt/${\beta}$-catenin 신호는 세포의 운명 결정, 증식, 분화 등을 조절하는 척추 동물 배아 발생과 성체의 항상성 유지에 필수적인 세포신호전달경로이다. 이러한 Wnt/${\beta}$-catenin의 비정상적인 조절에 의해 선천적 기형, 암, 대사질환 등을 비롯한 다양한 질병이 유발된다. 이를 바탕으로 최근 Wnt/${\beta}$-catenin 신호의 조절을 통한 암을 비롯한 질병의 치료를 위한 연구가 활발히 진행되고 있다. 따라서 Wnt/${\beta}$-catenin 신호를 조절하는 인자의 발굴 및 자세한 작용 기전에 대한 연구가 절실히 필요하다. 본 총설에서는 최근 새롭게 알려진 Wnt/${\beta}$-catenin 신호 조절 기작에 대해 설명하고, 현재까지 알려진 Wnt/${\beta}$조절하는 인산화 효소(kinase)의 종류와 작용 기전과 새로운 약물 타겟으로 전망을 알아 보고자 한다.

Keywords

References

  1. Bilic, J., Huang, Y. L., Davidson, G., Zimmermann, T., Cruciat, C. M., Bienz, M. and Niehrs, C. 2007. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 316, 1619-1622. https://doi.org/10.1126/science.1137065
  2. Chen, M., Philipp, M., Wang, J., Premont, R. T., Garrison, T. R., Caron, M. G., Lefkowitz, R. J. and Chen, W. 2009. G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J Biol Chem 284, 35040-35048. https://doi.org/10.1074/jbc.M109.047456
  3. Clevers, H. and Nusse, R. 2012. Wnt/beta-catenin signaling and disease. Cell 149, 1192-1205. https://doi.org/10.1016/j.cell.2012.05.012
  4. Cong, F., Schweizer, L. and Varmus, H. 2004. Casein kinase Iepsilon modulates the signaling specificities of dishevelled. Mol Cell Biol 24, 2000-2011. https://doi.org/10.1128/MCB.24.5.2000-2011.2004
  5. Dajani, R., Fraser, E., Roe, S. M., Yeo, M., Good, V. M., Thompson, V., Dale, T. C. and Pearl, L. H. 2003. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J 22, 494-501. https://doi.org/10.1093/emboj/cdg068
  6. Davidson, G., Shen, J., Huang, Y. L., Su, Y., Karaulanov, E., Bartscherer, K., Hassler, C., Stannek, P., Boutros, M. and Niehrs, C. 2009. Cell cycle control of wnt receptor activation. Dev Cell 17, 788-799. https://doi.org/10.1016/j.devcel.2009.11.006
  7. Davidson, G., Wu, W., Shen, J., Bilic, J., Fenger, U., Stannek, P., Glinka, A. and Niehrs, C. 2005. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867-872. https://doi.org/10.1038/nature04170
  8. Fang, D., Hawke, D., Zheng, Y., Xia, Y., Meisenhelder, J., Nika, H., Mills, G. B., Kobayashi, R., Hunter, T. and Lu, Z. 2007. Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem 282, 11221-11229. https://doi.org/10.1074/jbc.M611871200
  9. Gao, Y. and Wang, H. Y. 2006. Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling. J Biol Chem 281, 18394-18400. https://doi.org/10.1074/jbc.M601112200
  10. Gao, Z. H., Seeling, J. M., Hill, V., Yochum, A. and Virshup, D. M. 2002. Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proc Natl Acad Sci USA 99, 1182-1187. https://doi.org/10.1073/pnas.032468199
  11. Gonzalez-Sancho, J. M., Greer, Y. E., Abrahams, C. L., Takigawa, Y., Baljinnyam, B., Lee, K. H., Lee, K. S., Rubin, J. S. and Brown, A. M. 2013. Functional consequences of Wnt-induced dishevelled 2 phosphorylation in canonical and noncanonical Wnt signaling. J Biol Chem 288, 9428-9437. https://doi.org/10.1074/jbc.M112.448480
  12. Gwak, J., Cho, M., Gong, S. J., Won, J., Kim, D. E., Kim, E. Y., Lee, S. S., Kim, M., Kim, T. K., Shin, J. G. and Oh, S. 2006. Protein-kinase-C-mediated beta-catenin phosphorylation negatively regulates the Wnt/beta-catenin pathway. J Cell Sci 119, 4702-4709. https://doi.org/10.1242/jcs.03256
  13. Hammerlein, A., Weiske, J. and Huber, O. 2005. A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor- 1/beta-catenin complex. Cell Mol Life Sci 62, 606-618. https://doi.org/10.1007/s00018-005-4507-7
  14. Hart, M., Concordet, J. P., Lassot, I., Albert, I., del los Santos, R., Durand, H., Perret, C., Rubinfeld, B., Margottin, F., Benarous, R. and Polakis, P. 1999. The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol 9, 207-210. https://doi.org/10.1016/S0960-9822(99)80091-8
  15. Hikasa, H., Ezan, J., Itoh, K., Li, X., Klymkowsky, M. W. and Sokol, S. Y. 2010. Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification. Dev Cell 19, 521-532. https://doi.org/10.1016/j.devcel.2010.09.005
  16. Hikasa, H. and Sokol, S. Y. 2011. Phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2. J Biol Chem 286, 12093-12100. https://doi.org/10.1074/jbc.M110.185280
  17. Hino, S., Tanji, C., Nakayama, K. I. and Kikuchi, A. 2005. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol 25, 9063-9072. https://doi.org/10.1128/MCB.25.20.9063-9072.2005
  18. Huang, H. and He, X. 2008. Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol 20, 119-125. https://doi.org/10.1016/j.ceb.2008.01.009
  19. Huang, X., McGann, J. C., Liu, B. Y., Hannoush, R. N., Lill, J. R., Pham, V., Newton, K., Kakunda, M., Liu, J., Yu, C., Hymowitz, S. G., Hongo, J. A., Wynshaw-Boris, A., Polakis, P., Harland, R. M. and Dixit, V. M. 2013. Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling. Science 339, 1441-1445. https://doi.org/10.1126/science.1232253
  20. Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S. and Kikuchi, A. 1998. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J 17, 1371-1384. https://doi.org/10.1093/emboj/17.5.1371
  21. Ishitani, T., Ninomiya-Tsuji, J. and Matsumoto, K. 2003. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol 23, 1379-1389. https://doi.org/10.1128/MCB.23.4.1379-1389.2003
  22. Ishitani, T., Ninomiya-Tsuji, J., Nagai, S., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H. and Matsumoto, K. 1999. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399, 798-802. https://doi.org/10.1038/21674
  23. Kang, D. E., Soriano, S., Xia, X., Eberhart, C. G., De Strooper, B., Zheng, H. and Koo, E. H. 2002. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 110, 751-762. https://doi.org/10.1016/S0092-8674(02)00970-4
  24. Kibardin, A., Ossipova, O. and Sokol, S. Y. 2006. Metastasis-associated kinase modulates Wnt signaling to regulate brain patterning and morphogenesis. Development 133, 2845-2854. https://doi.org/10.1242/dev.02445
  25. Kikuchi, K., Niikura, Y., Kitagawa, K. and Kikuchi, A. 2010. Dishevelled, a Wnt signalling component, is involved in mitotic progression in cooperation with Plk1. EMBO J 29, 3470-3483. https://doi.org/10.1038/emboj.2010.221
  26. Klimowski, L. K., Garcia, B. A., Shabanowitz, J., Hunt, D. F. and Virshup, D. M. 2006. Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signaling. FEBS J 273, 4594-4602. https://doi.org/10.1111/j.1742-4658.2006.05462.x
  27. Lee, E., Salic, A. and Kirschner, M. W. 2001. Physiological regulation of [beta]-catenin stability by Tcf3 and CK1epsilon. J Cell Biol 154, 983-993. https://doi.org/10.1083/jcb.200102074
  28. Li, V. S., Ng, S. S., Boersema, P. J., Low, T. Y., Karthaus, W. R., Gerlach, J. P., Mohammed, S., Heck, A. J., Maurice, M. M., Mahmoudi, T. and Clevers, H. 2012. Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell 149, 1245-1256. https://doi.org/10.1016/j.cell.2012.05.002
  29. Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G. H., Tan, Y., Zhang, Z., Lin, X. and He, X. 2002. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837-847. https://doi.org/10.1016/S0092-8674(02)00685-2
  30. Luo, W. and Lin, S. C. 2004. Axin: a master scaffold for multiple signaling pathways. Neurosignals 13, 99-113. https://doi.org/10.1159/000076563
  31. MacDonald, B. T., Tamai, K. and He, X. 2009. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17, 9-26. https://doi.org/10.1016/j.devcel.2009.06.016
  32. MacDonald, B. T., Yokota, C., Tamai, K., Zeng, X. and He, X. 2008. Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J Biol Chem 283, 16115-16123. https://doi.org/10.1074/jbc.M800327200
  33. McKay, R. M., Peters, J. M. and Graff, J. M. 2001. The casein kinase I family in Wnt signaling. Dev Biol 235, 388-396. https://doi.org/10.1006/dbio.2001.0308
  34. Mosimann, C., Hausmann, G. and Basler, K. 2009. Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol 10, 276-286. https://doi.org/10.1038/nrm2654
  35. Nusse, R. and Varmus, H. E. 1982. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99-109. https://doi.org/10.1016/0092-8674(82)90409-3
  36. Pan, W., Choi, S. C., Wang, H., Qin, Y., Volpicelli-Daley, L., Swan, L., Lucast, L., Khoo, C., Zhang, X., Li, L., Abrams, C. S., Sokol, S. Y. and Wu, D. 2008. Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation. Science 321, 1350-1353. https://doi.org/10.1126/science.1160741
  37. Rubinfeld, B., Albert, I., Porfiri, E., Fiol, C., Munemitsu, S. and Polakis, P. 1996. Binding of GSK3beta to the APC-beta- catenin complex and regulation of complex assembly. Science 272, 1023-1026. https://doi.org/10.1126/science.272.5264.1023
  38. Rubinfeld, B., Tice, D. A. and Polakis, P. 2001. Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase 1epsilon. J Biol Chem 276, 39037-39045. https://doi.org/10.1074/jbc.M105148200
  39. Satow, R., Shitashige, M., Jigami, T., Honda, K., Ono, M., Hirohashi, S. and Yamada, T. 2010. Traf2- and Nck-interacting kinase is essential for canonical Wnt signaling in Xenopus axis formation. J Biol Chem 285, 26289-26294. https://doi.org/10.1074/jbc.M109.090597
  40. Song, D. H., Dominguez, I., Mizuno, J., Kaut, M., Mohr, S. C. and Seldin, D. C. 2003. CK2 phosphorylation of the armadillo repeat region of beta-catenin potentiates Wnt signaling. J Biol Chem 278, 24018-24025. https://doi.org/10.1074/jbc.M212260200
  41. Sun, T. Q., Lu, B., Feng, J. J., Reinhard, C., Jan, Y. N., Fantl, W. J. and Williams, L. T. 2001. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nat Cell Biol 3, 628-636. https://doi.org/10.1038/35083016
  42. Suzuki, A., Ozono, K., Kubota, T., Kondou, H., Tachikawa, K. and Michigami, T. 2008. PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J Cell Biochem 104, 304-317. https://doi.org/10.1002/jcb.21626
  43. Swiatek, W., Kang, H., Garcia, B. A., Shabanowitz, J., Coombs, G. S., Hunt, D. F. and Virshup, D. M. 2006. Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. J Biol Chem 281, 12233-12241. https://doi.org/10.1074/jbc.M510580200
  44. Tamai, K., Zeng, X., Liu, C., Zhang, X., Harada, Y., Chang, Z. and He, X. 2004. A mechanism for Wnt coreceptor activation. Mol Cell 13, 149-156. https://doi.org/10.1016/S1097-2765(03)00484-2
  45. Taurin, S., Sandbo, N., Qin, Y., Browning, D. and Dulin, N. O. 2006. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem 281, 9971-9976. https://doi.org/10.1074/jbc.M508778200
  46. Tian, Q., Feetham, M. C., Tao, W. A., He, X. C., Li, L., Aebersold, R. and Hood, L. 2004. Proteomic analysis identifies that 14-3-3zeta interacts with beta-catenin and facilitates its activation by Akt. Proc Natl Acad Sci USA 101, 15370-15375. https://doi.org/10.1073/pnas.0406499101
  47. Wallingford, J. B. and Habas, R. 2005. The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132, 4421-4436. https://doi.org/10.1242/dev.02068
  48. Wan, M., Yang, C., Li, J., Wu, X., Yuan, H., Ma, H., He, X., Nie, S., Chang, C. and Cao, X. 2008. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev 22, 2968-2979. https://doi.org/10.1101/gad.1702708
  49. Wang, S. and Jones, K. A. 2006. CK2 controls the recruitment of Wnt regulators to target genes in vivo. Curr Biol 16, 2239-2244. https://doi.org/10.1016/j.cub.2006.09.034
  50. Willert, K., Brink, M., Wodarz, A., Varmus, H. and Nusse, R. 1997. Casein kinase 2 associates with and phosphorylates dishevelled. EMBO J 16, 3089-3096. https://doi.org/10.1093/emboj/16.11.3089
  51. Willert, K. and Jones, K. A. 2006. Wnt signaling: is the party in the nucleus? Genes Dev 20, 1394-1404. https://doi.org/10.1101/gad.1424006
  52. Willert, K., Shibamoto, S. and Nusse, R. 1999. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex. Genes Dev 13, 1768-1773. https://doi.org/10.1101/gad.13.14.1768
  53. Wu, X., Tu, X., Joeng, K. S., Hilton, M. J., Williams, D. A. and Long, F. 2008. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell 133, 340-353. https://doi.org/10.1016/j.cell.2008.01.052
  54. Xing, Y., Clements, W. K., Kimelman, D. and Xu, W. 2003. Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex. Genes Dev 17, 2753-2764. https://doi.org/10.1101/gad.1142603
  55. Yamamoto, H., Kishida, S., Kishida, M., Ikeda, S., Takada, S. and Kikuchi, A. 1999. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem 274, 10681-10684. https://doi.org/10.1074/jbc.274.16.10681
  56. Yost, C., Torres, M., Miller, J. R., Huang, E., Kimelman, D. and Moon, R. T. 1996. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10, 1443-1454. https://doi.org/10.1101/gad.10.12.1443
  57. Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., Almeida, K., Wang, J., Doble, B., Woodgett, J., Wynshaw-Boris, A., Hsieh, J. C. and He, X. 2008. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/ activation via frizzled, dishevelled and axin functions. Development 135, 367-375.
  58. Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J. and He, X. 2005. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873-877. https://doi.org/10.1038/nature04185
  59. Zhang, J., Yang, P. L. and Gray, N. S. 2009. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9, 28-39. https://doi.org/10.1038/nrc2559
  60. Zhang, L., Jia, J., Wang, B., Amanai, K., Wharton, K. A., Jr. and Jiang, J. 2006. Regulation of wingless signaling by the CKI family in Drosophila limb development. Dev Biol 299, 221-237. https://doi.org/10.1016/j.ydbio.2006.07.025